Project Summary/Abstract Cognitive impairments may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Cognitive impairments may go away soon after chemotherapy is over or may persist for years and yet, there is a paucity of effective treatments. Research has shown that chemotherapy drugs such as doxorubicin directly disturb synaptic structure by altering its biochemistry. For example, doxorubicin activate N-methyl D-aspartate (NMDA) receptors leading to neurotoxicity and accelerated neuronal aging. Critically, some studies demonstrated that dementia occurs more commonly in cancer patients who had chemotherapy treatment compared to individuals never exposed to chemotherapy. A search for druggable targets for treating chemobrain led us to hypothesize that inhibiting an enzyme called NAAG peptidase (NAAGP) may reduce toxicity associated with chemotherapy. NAAGP catalyzes the hydrolysis of a neuropeptide N-acetylaspartylglutamate (NAAG) to N-acetylaspartate and an excitatory neurotransmitter glutamate, which may contribute to NMDA-dependent excitotoxicity. In our data, we show that doxorubicin enhances the deposition of amyloid in Tg2576 mice, a model of Alzheimer?s disease. We also demonstrate that ZJ43, an inhibitor of NAAGP, mitigates doxorubicin-induced cognitive impairment in wild-type mice. Therefore, manipulating the NAAG peptidase pathway may be a therapy against cognitive impairments associated with chemotherapy. Manipulating NAAGP may also prevent accelerated brain aging and dementia associated with chemotherapy treatment. In this proposal, we will determine whether ZJ43 alleviates cognitive and behavioral phenotypes and improves pathology in Tg2576 and Tau P301S mice treated with doxorubicin. A successful implementation of the goals of our proposal will bring us closer to developing a therapy for doxorubicin-associated cognitive disturbances and dementia, and help us to improve the life quality of cancer patients and survivors.